Citations

SNF'ing out antitumor immunity Immune checkpoint inhibitors induce durable tumor regressions in some, but not all, cancer patients. Understanding the mechanisms that determine tumor sensitivity to these drugs could potentially expand the number of patients who benefit (see the Perspective by Ghorani and Quezada). Pan et al. discovered that tumor cells in which a specific SWI/SNF chromatin remodeling complex had been experimentally inactivated were more sensitive to T cell–mediated killing. The cells were more responsive to interferon-γ, leading to increased secretion of cytokines that promote antitumor immunity. Miao et al. examined the genomic features of tumors from patients with metastatic renal cell carcinoma who had been treated with immune checkpoint inhibitors. Tumors harboring inactivating mutations in PBRM1 , which encodes a subunit of the same SWI/SNF complex, were more likely to respond to the drugs. Science , this issue p. 770 , p. 801 ; see also p. 745

Fredberg, J. J., K. A. Jones, M. Nathan, S. Raboudi, Y. S. Prakash, S. A. Shore, J. P. Butler, and G. C. Sieck. Friction in airway smooth muscle: mechanism, latch, and implications in asthma. J. Appl. Physiol. 81(6): 2703–2712, 1996.—In muscle, active force and stiffness reflect numbers of actin-myosin interactions and shortening velocity reflects their turnover rates, but the molecular basis of mechanical friction is somewhat less clear. To better characterize molecular mechanisms that govern mechanical friction, we measured the rate of mechanical energy dissipation and the rate of actomyosin ATP utilization simultaneously in activated canine airway smooth muscle subjected to small periodic stretches as occur in breathing. The amplitude of the frictional stress is proportional to ηE, where E is the tissue stiffness defined by the slope of the resulting force vs. displacement loop and η is the hysteresivity defined by the fatness of that loop. From contractile stimulus onset, the time course of frictional stress amplitude followed a biphasic pattern that tracked that of the rate of actomyosin ATP consumption. The time course of hysteresivity, however, followed a different biphasic pattern that tracked that of shortening velocity. Taken together with an analysis of mechanical energy storage and dissipation in the cross-bridge cycle, these results indicate, first, that like shortening velocity and the rate of actomyosin ATP utilization, mechanical friction in airway smooth muscle is also governed by the rate of cross-bridge cycling; second, that changes in cycling rate associated with conversion of rapidly cycling cross bridges to slowly cycling latch bridges can be assessed from changes of hysteresivity of the force vs. displacement loop; and third, that steady-state force maintenance (latch) is a low-friction contractile state. This last finding may account for the unique inability of asthmatic patients to reverse spontaneous airways obstruction with a deep inspiration.

BACKGROUNDUpdated knowledge of the palliative care (PC) literature is needed to maintain competency and best address the PC needs of hospitalized patients. We critiqued the recent PC literature with the highest potential to impact hospital practice.METHODSWe reviewed articles published between January 2016 and December 2016, which were identified through a handsearch of leading journals and a MEDLINE search. The final 9 articles selected were determined by consensus based on scientific rigor, relevance to hospital medicine, and impact on practice.RESULTSKey findings include the following: scheduled antipsychotics were inferior to a placebo for nonterminal delirium; a low‐dose morphine was superior to a weak opioid for moderate cancer pain; methadone as a coanalgesic improved high‐intensity cancer pain; many hospitalized patients on comfort care still receive antimicrobials; video decision aids improved the rates of advance care planning (ACP) and hospice use and decreased costs; standardized, PC‐led intervention did not improve psychological outcomes in families of patients with a chronic critical illness; caregivers of patients surviving a prolonged critical illness experienced high and persistent rates of depression; people with non‐normative sexuality or gender faced additional stressors with partner loss; and physician trainees experienced significant moral distress with futile treatments.CONCLUSIONSRecent research provides important guidance for clinicians caring for hospitalized patients with serious illnesses, including symptom management, ACP, moral distress, and outcomes of critical illness.

Glioblastoma (GBM) is the most common primary intracranial neoplasia, and is characterized by its extremely poor prognosis. Despite maximum surgery, chemotherapy, and radiation, the histological heterogeneity of GBM makes total eradication impossible, due to residual cancer cells invading the parenchyma, which is not otherwise seen in radiographic images. Even with gross total resection, the heterogeneity and the dormant nature of brain tumor initiating cells allow for therapeutic evasion, contributing to its recurrence and malignant progression, and severely impacting survival. Visual delimitation of the tumor’s margins with common surgical techniques is a challenge faced by many surgeons. In an attempt to achieve optimal safe resection, advances in approaches allowing intraoperative analysis of cancer and non-cancer tissue have been developed and applied in humans resulting in improved outcomes. In addition, functional paradigms based on stimulation techniques to map the brain’s electrical activity have optimized glioma resection in eloquent areas such as the Broca’s, Wernike’s and perirolandic areas. In this review, we will elaborate on the current standard therapy for newly diagnosed and recurrent glioblastoma with a focus on surgical approaches. We will describe current technologies used for glioma resection, such as awake craniotomy, fluorescence guided surgery, laser interstitial thermal therapy and intraoperative mass spectrometry. Additionally, we will describe a newly developed tool that has shown promising results in preclinical experiments for brain cancer: optical coherence tomography.

Development of late-onset respiratory diseases is associated with elevated 8-isoprostane, a marker of oxidative stress, in the airways. However, sex differences exist in development of these diseases. Using an exhaustive exercise bout as a physiological stressor may elucidate whether there is a sex difference with aging in pre- to postexercise airway 8-isoprostane generation. The purpose of this study was to determine whether older women exhibit a greater airway 8-isoprostane response to exhaustive exercise compared with older men and younger controls. Thirty-six individuals completed the study (12 postmenopausal older women (OW) and 12 age-matched older men (OM), 65 ± 4 years of age; and 12 younger controls (YC), 21 ± 2 years of age). Baseline measurements included exhaled breath condensate (EBC) for assessment of airway 8-isoprostane and standard pulmonary function tests (PFTs) to assess forced expiratory volume in 1-s (FEV1), forced vital capacity (FVC), FEV1/FVC, and forced expiratory flow at 25%–75% of FVC. Subjects then performed a peak oxygen uptake test to exhaustion on a cycle ergometer. Immediately postexercise, PFTs and EBC were performed. The generation of airway 8-isoprostane from pre- to postexercise was greater in OW compared with OM and YC (p < 0.01), increasing ∼74% ± 77% in OW, while decreasing in OM (∼12% ± 50%) and YC (∼20.9% ± 30%). The OW exhibited a greater airway 8-isoprostane response to exhaustive exercise compared with OM and YC, which may suggest that sex differences in oxidative stress generation following exhaustive exercise may provide a mechanistic rationale for sex differences in late-onset respiratory diseases.

Objectives To assess the degree to which self‐reported symptoms predict unplanned readmission or emergency department ( ED ) care within 30 days of high‐risk, elderly adults enrolled in a posthospitalization care transition program ( CTP ). Design Retrospective cohort study. Setting Posthospitalization CTP at Mayo Clinic, Rochester, Minnesota, from January 1, 2013, through March 3, 2015. Participants Frail, elderly adults (N = 230; mean age 83.5 ± 8.3, 46.5% male). Measurements Charlson Comorbidity Index ( CCI ) and self‐reported symptoms, measured using the Edmonton Symptom Assessment System ( ESAS ), were ascertained upon CTP enrollment. Results Mean CCI was 3.9 ± 2.3. Of 51 participants returning to the hospital within 30 days of discharge, 13 had ED visits, and 38 were readmitted. Age, sex, and CCI were not significantly different between returning and nonreturning participants, but returning participants were significantly more likely to report shortness of breath ( P = .004), anxiety ( P = .02), depression ( P = .02), and drowsiness ( P = .01). Overall ESAS score was also a significant predictor of hospital return ( P = .01). Conclusion Four self‐reported symptoms and overall ESAS score, but not CCI , ascertained after hospital discharge were strong predictors of hospital return within 30 days. Including symptoms in risk stratification of high‐risk elderly adults may help target interventions and reduce readmissions.

AimsThe primary aim of this study was to define the standard minimum follow-up required to produce a reliable estimate of the rate of re-operation after radial head arthroplasty (RHA). The secondary objective was to define the leading reasons for re-operation.Materials and MethodsFour electronic databases, between January 2000 and March 2017 were searched. Articles reporting reasons for re-operation (Group I) and results (Group II) after RHA were included. In Group I, a meta-analysis was performed to obtain the standard minimum follow-up, the mean time to re-operation and the reason for failure. In Group II, the minimum follow-up for each study was compared with the standard minimum follow-up.ResultsA total of 40 studies were analysed: three were Group I and included 80 implants and 37 were Group II and included 1192 implants. In Group I, the mean time to re-operation was 1.37 years (0 to 11.25), the standard minimum follow-up was 3.25 years; painful loosening was the main indication for re-operation. In Group II, 33 Group II articles (89.2%) reported a minimum follow-up of < 3.25 years.ConclusionThe literature does not provide a reliable estimate of the rate of re-operation after RHA. The reproducibility of results would be improved by using a minimum follow-up of three years combined with a consensus of the definition of the reasons for failure after RHA. Cite this article: Bone Joint J 2017;99-B:1561–70.